ENDOCRINE SYSTEM

PITUITARY GLAND AND THYROID GLAND

PITUITARY GLAND- INTRODUCTION
 The pituitary gland is a small, bean-shaped structure
that lies at the base of the brain within the sella turcica.
 Its function is controlled by the hypothalamus, to which

it is connected by a stalk containing axons extending

from the hypothalamus and a rich venous plexus.
 Along with the hypothalamus, the pituitary has a central

role in regulating the function of most of the other

endocrine glands.
 The pituitary gland is composed of two morphologically

and functionally distinct components: the anterior lobe

(adenohypophysis) and the posterior lobe
(neurohypophysis).
Cont’
 There are six terminally differentiated cell types in the anterior
pituitary, each of which is defined by the hormones that it
synthesizes:
 Somatotrophs produce growth hormone (GH).
 Mammosomatotrophs produce GH and prolactin (PRL).
 Lactotrophs produce PRL.
 Corticotrophs produce adrenocorticotropic hormone (ACTH),
pro-opiomelanocortin (POMC), and melanocytestimulating
hormone (MSH).
 Thyrotrophs produce thyroid-stimulating hormone (TSH).
 Gonadotrophs produce follicle-stimulating hormone (FSH) and
Liutnizing hormone(LH).
 Two peptide hormones are secreted from the posterior pituitary,
oxytocin and ADH.
CLINICAL MANIFESTATIONS OF
PITUITARY DISEASE
• Hyperpituitarism arises from excess secretion of trophic
hormones. The causes of hyperpituitarism include
hyperplasias, adenomas, and carcinomas of the anterior
pituitary, secretion of hormones by nonpituitary tumors, and
certain hypothalamic disorders.
 Hypopituitarism results from deficiency of trophic hormones.

It may be caused by ischemic injury, surgery or radiation,

inflammatory disorders, and the mass effects of
nonfunctional pituitary adenomas.
 Symptoms related to local mass effects. Because of proximity

of optic nerves and tract to the sella, visual abnormalities may

arise when these structures are compressed. Symptoms of
elevated intracranial pressure such as headache, nausea and
vomiting.
1. PITUITARY ADENOMAS AND
HYPERPITUITARISM.
 The most common cause of hyperpituitarism is
an adenoma arising in the anterior lobe. Pituitary
adenomas are classified on the basis of the
hormones and cell type–specific transcription
factors that are expressed by the tumor cells.
 Some pituitary adenomas secrete two hormones
(GH and prolactin being the most common
combination), and rarely, pituitary adenomas are
plurihormonal. Less common causes of
hyperpituitarism include pituitary carcinomas
and some hypothalamic disorders.
Cont’
 By contrast, large pituitary adenomas, and
particularly nonfunctioning ones, may cause
hypopituitarism by destroying the adjacent
normal anterior pituitary parenchyma.
Pituitary adenomas are usually found in
adults; the peak incidence is from 35 to 60
years of age. They are designated, somewhat
arbitrarily, microadenomas if they are less
than 1 cm in diameter and macroadenomas if
they exceed 1 cm in diameter.
PATHOGENESIS
 As with other neoplasms, pituitary adenomas are caused
by mutations in cancer genes, which are most commonly
acquired somatic mutations but which may also be
germline mutations associated with an inherited
predisposition to pituitary neoplasms .
 Activating G-protein mutations are one of the most
common alterations in pituitary adenomas.
 Activating mutations of ubiquitin-specific protease 8
(USP8) also occur in 30% to 60% of corticotroph
adenomas.
 Approximately 5% of pituitary adenomas are caused by
germline loss-of-function mutations in genes such as
MEN1, CDKN1B, PRKAR1A, or AIP.
MORPHOLOGY
 The typical pituitary adenoma is soft and well-circumscribed. Small
adenomas may be confined to the sella turcica, but with expansion
they frequently erode the sella turcica and anterior clinoid
processes. Larger lesions may extend superiorly through the
diaphragm sella into the suprasellar region.
 In as many as 30% of cases, the adenomas are not encapsulated
and infiltrate neighboring tissues such as the cavernous and
sphenoid sinuses, dura, and on occasion, the brain itself. Such
lesions are termed aggressive adenomas. Not unexpectedly,
macroadenomas are more likely to be invasive and to have foci of
hemorrhage and necrosis.
 Histologically, typical pituitary adenomas are composed of uniform
(monomorphic), polygonal cells arrayed in sheets or cords.
 The supporting connective tissue, or reticulin, is sparse, accounting
for the soft, gelatinous consistency of many of these tumors.
Lactotroph Adenoma
 Prolactin-secreting lactotroph adenomas are the most common type of
hyperfunctioning pituitary adenoma, accounting for about 30% of clinically
recognized cases. These lesions range from small microadenomas to large,
expansile tumors associated with symptomatic mass effects.
 Morphology: The large majority of lactotroph adenomas are composed of

chromophobe cells with juxtanuclear localization of the transcription factor

PIT-1; these are known as sparsely granulated lactotroph adenomas.
 Much rarer are the eosinophilic densely granulated lactotroph adenomas,

characterized by diffuse cytoplasmic PIT-1 localization. Prolactin can be

demonstrated within cytoplasmic secretory granules with
immunohistochemical stains, and estrogen receptor alpha (ERα) is co-
expressed along with PIT-1, consistent with lactotroph differentiation.
 Lactotroph adenomas often undergo dystrophic calcification, ranging from

isolated psammoma bodies to extensive calcification (“pituitary stone”).

Prolactin secretion by functioning adenomas is usually efficient and
proportional, in that serum prolactin concentrations tend to correlate with
the size of the adenoma.
Clinical features
 Increased serum levels of prolactin, or prolactinemia, cause amenorrhea,
galactorrhea, loss of libido, and infertility.
 Hyperprolactinemia may result from causes other than prolactin-secreting
pituitary adenomas. Physiologic hyperprolactinemia occurs in pregnancy.
 Pathologic hyperprolactinemia can also result from lactotroph hyperplasia
caused by loss of dopamine-mediated inhibition of prolactin secretion. This
may occur due to damage of the dopaminergic neurons of the hypothalamus
or the pituitary stalk (e.g., due to head trauma), or exposure to drugs that
block dopamine receptors on lactotroph cells.
 Any suprasellar mass (e.g., a pituitary adenoma) may disturb the inhibitory
influence of the hypothalamus on prolactin secretion, resulting in
hyperprolactinemia. Therefore, mild hyperprolactenemia in a person with a
pituitary adenoma does not necessarily indicate a prolactin-secreting tumor.
Other causes of hyperprolactinemia include renal failure and hypothyroidism.
 Lactotroph adenomas are treated by surgery or, more commonly, with
bromocriptine, a dopamine receptor agonist that causes the lesions to
diminish in size.
Somatotroph Adenoma
 Growth hormone (GH)-secreting somatotroph adenomas are the second most
common type of functioning pituitary adenoma, and cause gigantism in
children and acromegaly in adults.
 Morphology. Histologically, pure somatotroph adenomas are also classified
into densely granulated and sparsely granulated subtypes. Densely granulated
somatotroph adenomas are composed of monomorphic, eosinophilic cells with
granular cytoplasm and a large central nucleus with prominent nucleoli. The
cells have diffuse, strong immunoreactivity for GH. In contrast, the sparsely
granulated variants are composed of chromophobe cells with patchy, weak
staining for GH and a characteristic paranuclear glossy inclusion known as a
fibrous body, composed of intermediate filaments that stain for cytokeratin.
 Bihormonal mammosomatotroph adenomas that synthesize GH and prolactin
in the same cell are being increasingly recognized; morphologically, most
resemble densely granulated somatotroph adenomas, but have
immunohistochemical reactivity for prolactin and GH. These are to be
contrasted with mixed somatotroph-lactotroph adenomas, which have GH and
prolactin expression in different cell.
Clinical features
 Persistently elevated levels of GH stimulate the hepatic secretion of insulin-
like growth factor-1 (IGF-1), which causes many of the clinical
manifestations.
 If a somatotroph adenoma appears in children before the epiphyses have

closed, the elevated levels of GH (and IGF-1) result in gigantism. This is

characterized by a generalized increase in body size with disproportionately
long arms and legs.
 If the levels of GH are increased after closure of the epiphyses, acromegaly

develops. In this condition, growth is most conspicuous in skin and soft

tissues, viscera (thyroid, heart, liver, and adrenals), and the bones of the
face, hands, and feet.
 GH excess can also be associated with a variety of other disturbances,

including gonadal dysfunction, diabetes mellitus, generalized muscle

weakness, hypertension, arthritis, congestive heart failure, and an increased
risk of gastrointestinal cancers.
 The pituitary adenoma can be removed surgically or treated by

pharmacologic means.
Corticotroph Adenoma
 Excess production of ACTH by functioning corticotroph adenomas
leads to adrenal hypersecretion of cortisol and the development of
hypercortisolism (also known as Cushing syndrome).
 Morphology. Corticotroph adenomas are usually microadenomas at
the time of diagnosis. These tumors are most often basophilic
(densely granulated) and occasionally chromophobic
(sparselygranulated). Both variants stain positively with periodic
acid-Schiff (PAS) because of the presence of carbohydrate in
proopiomelanocortin (POMC), the precursor of ACTH. Nuclear TPIT
is also positive in the neoplastic cells, consistent with corticotroph
lineage.
 A third uncommon variant, called Crooke cell adenoma, is
characterized by ringlike deposition of cytokeratin called Crooke
change. This variant has an aggressive natural history compared
with other subtypes of corticotroph adenomas.
Clinical features
 Cushing syndrome can be caused by a wide variety of conditions
in addition to ACTH-producing pituitary tumors. When the
hypercortisolism is due to excessive production of ACTH by the
pituitary, it is designated Cushing disease.
 Large destructive pituitary adenomas can develop in patients

after surgical removal of the adrenal glands for treatment of

Cushing syndrome. This condition, known as Nelson syndrome,
occurs because of loss of the inhibitory effect of adrenal
corticosteroids on a corticotroph microadenoma. Because the
adrenals are absent in persons with Nelson syndrome,
hypercortisolism does not develop.
 Patients present with mass effects due to the pituitary tumor, and

there can be hyperpigmentation because melanotropin, which

has trophic effects on melanocytes, is also derived from POMC.
Other Anterior Pituitary Tumors
 Gonadotroph (LH-producing and FSH-producing) adenomas can be difficult
to recognize because they secrete small amounts of hormones , most
frequently present in middle-aged men and women with neurologic
symptoms, such as impaired vision, headaches, diplopia, or pituitary
apoplexy. Pituitary hormone deficiencies can also be found, most
commonly impaired secretion of LH, which causes decreased energy and
libido in men (due to reduced testosterone) and amenorrhea in
premenopausal .
 Thyrotroph (TSH-producing) adenomas are uncommon, accounting for

approximately 1% of pituitary adenomas. They are a rare cause of

hyperthyroidism. Due to their shared lineage with lactotroph and
somatotroph adenomas, these tumors also express PIT-1.
 Pituitary adenomas may also secrete multiple hormones; such

“plurihormonal” adenomas are usually aggressive. Most are derived from

cells of PIT-1–expressing lineage.
 Null cell adenomas do not express any markers of hormonal or lineage

differentiation.
Cont’
 Pituitary carcinoma is rare, accounting for less than
1% of pituitary tumors.
 Pituitary blastoma is an entity that occurs in children

(typically younger than 2 years of age) who carry

germline mutations of DICER1, the gene encoding a
microRNAprocessing protein. Morphologically, these
tumors are composed of immature “blastema-like”
cells (so-called “small round blue cells”) and rosette-
like formations resembling the primitive Rathke
epithelium from which the pituitary develops.
 Pituitary blastoma presents with signs and

symptoms of Cushing disease.

HYPOPITUITARISM
 Hypopituitarism refers to decreased secretion of pituitary hormones, which
can result from diseases of the hypothalamus or of the pituitary. Most
cases of hypopituitarism arise from destructive processes involving the
anterior pituitary, as follows:
 Tumors and other mass lesions:Any mass lesion in the sella can cause
damage by exerting pressure on adjacent normal pituitary cells.
 Traumatic brain injury and subarachnoid hemorrhage.
 Pituitary surgery or radiation
 Pituitary apoplexy
 Ischemic necrosis of the pituitary (Sheehan syndrome)
 Rathke cleft cyst
 Empty sella syndrome: Any condition or treatment that destroys part or all
of the pituitary gland.
 Hypothalamic lesions
 Inflammatory disorders and infections
 Genetic defects
Clinical features
 The clinical manifestations of anterior pituitary hypofunction vary
depending on the specific hormones that are lacking.
 Children can develop growth failure (pituitary dwarfism) due to
growth hormone deficiency.
 Gonadotropin (LH and FSH) deficiency leads to amenorrhea and
infertility in women and decreased libido, impotence, and loss of
pubic and axillary hair in men.
 TSH and ACTH deficiencies result in symptoms of hypothyroidism
and hypoadrenalism.
 Prolactin deficiency results in failure of postpartum lactation.
 The anterior pituitary is also a rich source of melanotropins (also
known as melanocyte-stimulating hormone), synthesized from the
same precursor molecule that produces ACTH; therefore, one of the
manifestations of hypopituitarism includes pallor due to a loss of
stimulatory effects on melanocytes.
POSTERIOR PITUITARY SYNDROMES
 The clinically relevant posterior pituitary syndromes involve ADH and
include diabetes insipidus and syndrome of inappropriate secretion of
ADH.
 Diabetes insipidus. ADH deficiency causes diabetes insipidus, a
condition characterized by excessive urination (polyuria) due to an
inability of the kidney to resorb water properly from the urine.
Diabetes insipidus can occur in a variety of conditions, including head
trauma, tumors, inflammatory disorders of the hypothalamus and
pituitary, and surgical complications. Rarely, diabetes insipidus has a
genetic basis, either because of autosomal dominant mutations of the
arginine vasopressin (AVP) gene, or mutations of arginine vasopressin
receptor type 2 (AVPR2), an X-linked condition that usually presents in
young boys.
 Diabetes insipidus from ADH deficiency is designated as central to
differentiate it from nephrogenic diabetes insipidus, which is a result
of renal tubular unresponsiveness to circulating ADH.
Cont’
 The clinical manifestations of these two disorders are similar and include the
excretion of large volumes of dilute urine with a lower than normal specific
gravity. Serum sodium and osmolality are increased by the excessive renal
loss of free water, resulting in thirst and polydipsia. Patients who can drink
water generally compensate for the urinary losses, but patients who are
obtunded, bedridden, or otherwise limited in their ability to obtain water
may develop life-threatening dehydration.
 Syndrome of inappropriate ADH (SIADH) secretion. ADH excess causes over-

resorption of free water, resulting in hyponatremia. The most frequent

causes of SIADH are the secretion of ectopic ADH by malignant neoplasms
(particularly small-cell carcinoma of the lung), drugs that increase ADH
secretion, and a variety of central nervous system disorders, including
infections and trauma.
 The clinical manifestations of SIADH are dominated by hyponatremia,

cerebral edema, and resultant neurologic dysfunction. Although total body

water is increased, blood volume remains normal, and peripheral edema
does not develop.
HYPOTHALAMIC SUPRASELLAR
TUMORS.
 Neoplasms in this location may induce hypofunction or
hyperfunction of the anterior pituitary, diabetes insipidus, or
combinations of these manifestations. The most commonly
implicated tumors are glioma (sometimes arising in the
chiasm and craniopharyngioma).Craniopharyngioma is
thought to arise from vestigial remnants of Rathke pouch.
These slow-growing tumors account for 1% to 5% of
intracranial tumors. A small minority of these lesions occurs
within the sella, but most are suprasellar, with or without
intrasellar extension.
 Patients usually come to attention because of headaches and
visual disturbances, while children sometimes present with
growth retardation due to pituitary hypofunction and GH
deficiency.
Thyroid Gland
 The thyroid gland consists of two lateral lobes connected by a thin
isthmus, usually located below and anterior to the larynx.
 In response to hypothalamic factors, TSH (thyrotropin) is released
by thyrotrophs in the anterior pituitary into the circulation. The
binding of TSH to its receptor on thyroid follicular epithelial cells
activates the receptor, which then associates with a Gs protein.
Activation of the Gprotein triggers downstream events that increase
intracellular cAMP levels, which, in turn, stimulates thyroid growth
and thyroid hormone synthesis and release via cAMP-dependent
protein kinases.
 Thyroid follicular epithelial cells convert thyroglobulin into
thyroxine (T4) and lesser amounts of triiodothyronine (T3). T4 and
T3 are released into the systemic circulation where most of these
peptide hormones are reversibly bound to circulating plasma
proteins, such as thyroxine-binding globulin and transthyretin.
Cont’
Thyroid hormone has diverse cellular effects, including the stimulation of
carbohydrate and lipid catabolism and protein synthesis in a wide range of
cells. The net result is an increase in the basal metabolic rate. In addition,
thyroid hormone has a critical role in brain development in the fetus and
neonate.
The function of the thyroid gland can be inhibited by a variety of chemical

agents, collectively referred to as goitrogens. Because they suppress T3 and

T4 synthesis, the level of TSH increases, causing subsequent hyperplastic
enlargement of the gland (goiter). The antithyroid agent propylthiouracil
inhibits the oxidation of iodide and thus blocks the production of thyroid
hormones. Iodide, when given in large doses to individuals with thyroid
hyperfunction, blocks the release of thyroid hormones by inhibiting the
proteolysis of thyroglobulin.
 The thyroid gland follicles also contain a population of parafollicular cells, or

C cells, which synthesize and secrete the hormone calcitonin. This hormone
promotes the absorption of calcium by the skeletal system and inhibits the
resorption of bone by osteoclasts.
Hyperthyroidism
 Thyrotoxicosis is a hypermetabolic state caused by elevated circulating
levels of free T3 and T4.
 Disorders Associated With Thyrotoxicosis
 Associated With Hyperthyroidism :

1.Primary Diffuse hyperplasia (Graves disease).

2.Hyperfunctioning (“toxic”) multinodular goiter.
3.Hyperfunctioning (“toxic”) adenoma.
4.Iodine-induced hyperthyroidism.
5.Neonatal thyrotoxicosis associated with maternal Graves disease
6.Secondary TSH-secreting pituitary adenoma (rare)
 Not Associated With Hyperthyroidism.

1.Granulomatous (de Quervain) thyroiditis (painful)

2.Subacute lymphocytic thyroiditis (painless)
3.Struma ovarii (ovarian teratoma with ectopic thyroid)
4.Factitious thyrotoxicosis (exogenous thyroxine intake
Clinical features
 Excessive levels of thyroid hormone result in an increase in the basal metabolic rate. The skin of
thyrotoxic patients tends to be soft, warm, and flushed because of increased blood flow and
peripheral vasodilation, adaptations that serve to increase heat loss. Heightened catabolic
metabolism results in weight loss despite increased appetite.
 Cardiac manifestations. Individuals with hyperthyroidism can have elevated cardiac contractility

and output, a response to increased peripheral oxygen requirements. Tachycardia, palpitations,

and cardiomegaly are common. Heart failure may develop.
 Overactivity of the sympathetic nervous system produces tremor, hyperactivity, emotional lability,

anxiety, inability to concentrate, and insomnia. In the gastrointestinal system, hypermotility and
reduced transit times lead to hyperdefecation.
 Ocular changes. A wide, staring gaze and lid lag are present because of sympathetic

overstimulation of the superior tarsal muscle (also known as Müller’s muscle).

 The skeletal system . Thyroid hormone stimulates bone resorption, increasing cortical bone

porosity and reducing trabecular bone volume. The net effect is osteoporosis and an increased risk
of fractures.
 Thyroid storm refers to the abrupt onset of severe hyperthyroidism This condition occurs most

commonly in patients with Graves disease and probably results from an acute elevation in
catecholamine levels, as might beencountered during infection, surgery, cessation of antithyroid
medication, or any form of stress.
 Apathetic hyperthyroidism refers to thyrotoxicosis occurring in older adults, in whom advanced

age and various comorbidities blunt the typical features of thyroid hormone excess.
Hypothyroidism
 Hypothyroidism is a condition caused by a structural or
functional derangement that interferes with the
production of thyroid hormone.
 Hypothyroidism can result from a defect anywhere in the

hypothalamic-pituitary-thyroid axis. Like

hyperthyroidism, it can be divided into primary and
secondary forms, depending on whether it arises from an
intrinsic thyroid abnormality or as a result of pituitary
and hypothalamic disease .
 Primary hypothyroidism accounts for the vast majority of

cases and may be accompanied by enlargement of the

thyroid gland (goiter). Primary hypothyroidism can be
congenital, autoimmune, or iatrogenic.
Cont’
 Congenital hypothyroidism. Worldwide, congenital hypothyroidism is most often
the result of endemic iodine deficiency in the diet.Other rare forms of congenital
hypothyroidism include inborn errors of thyroid metabolism (dyshormonogenetic
goiter), wherein one of the several steps leading to thyroid hormone synthesis is
defective. In rare instances, there may be complete absence of thyroid
parenchyma (thyroid agenesis), or the gland may be greatly reduced in size
(thyroid hypoplasia) due to germline mutations in genes responsible for thyroid
development .
 Autoimmune hypothyroidism . Autoimmune hypothyroidism is the most common

cause of hypothyroidism in iodine sufficient areas of the world. The vast majority
of cases are due to Hashimoto thyroiditis. Circulating autoantibodies, including
antimicrosomal, antithyroid peroxidase, and antithyroglobulin antibodies, are
found in this disorder, and the thyroid is typically enlarged (goitrous).
 Iatrogenic hypothyroidism. This can be caused by either surgical or radiation-

induced ablation .
 Secondary (or central) hypothyroidism is caused by deficiencies of TSH or, far

more uncommonly, TRH.

Cretinism
 Cretinism refers to hypothyroidism that develops in infancy or early
childhood. In the past, this disorder occurred fairly commonly in regions of
the world where dietary iodine deficiency is endemic, such as the Himalayas,
inland China, Africa, and other mountainous areas.
 It is now much less prevalent as a result of the widespread supplementation

of foods with iodine. On rare occasions, cretinism results from genetic

defects that interfere with the biosynthesis of thyroid hormone
(dyshormonogenetic goiter).
 Clinical features of cretinism include severe intellectual disability, short

stature, coarse facial features, a protruding tongue, and umbilical hernia.

The severity of the mental impairment seems to be related to the time at
which thyroid deficiency occurs in utero. Normally, maternal T3 and T4 cross
the placenta and are critical for fetal brain development. If there is maternal
thyroid deficiency before the development of the fetal thyroid gland,
intellectual disability is severe. In contrast, maternal thyroid hormone
deficiency later in pregnancy, after the fetal thyroid has become functional,
does not affect normal brain development.
Myxedema
 The term myxedema is applied to hypothyroidism developing in the older
child or adult.
 Myxedema is marked by a slowing of physical and mental activity. Early

symptoms include generalized fatigue, apathy, and mental sluggishness,

which may mimic depression. Speech and intellectual functions are slowed,
and patients are listless, cold intolerant, and frequently overweight.
Decreased sympathetic activity results in constipation and decreased
sweating. The skin is cool and pale because of decreased blood flow.
Reduced cardiac output probably contributes to shortness of breath and
decreased exercise capacity, two frequent complaints.
 In addition, changes in lipid metabolism produce an increase in total

cholesterol and low-density lipoprotein (LDL) levels that is pro-atherogenic,

contributing to increased cardiovascular mortality.
 Histologically, there is an accumulation of matrix substances, such as

glycosaminoglycans and hyaluronic acid, in skin, subcutaneous tissue, and

visceral sites. This results in nonpitting edema, a broadening and coarsening
of facial features, enlargement of the tongue, and deepening of the voice.
THYROIDITIS
 Thyroiditis encompasses a diverse group of
disorders characterized by some form of
thyroid inflammation. :
 (1) Hashimoto thyroiditis,
 (2) granulomatous (de Quervain) thyroiditis,

and
 (3) subacute lymphocytic thyroiditis.
Hashimoto Thyroiditis
 Hashimoto thyroiditis is an autoimmune disease that results in destruction of the
thyroid gland and gradual and progressive thyroid failure.
 Pathogenesis Hashimoto thyroiditis is caused by a breakdown in self-tolerance to
thyroid autoantigens. This is exemplified by the presence of circulating
autoantibodies against thyroglobulin and thyroid peroxidase in the vast majority of
patients. The inciting events have not been elucidated, but possibilities include
abnormalities of regulatory T cells (Tregs), or exposure of normally sequestered
thyroid antigens. Induction of thyroid autoimmunity is accompanied by a progressive
depletion of thyroid epithelial cells and replacement of the thyroid parenchyma by
lymphocytic infiltrates and fibrosis.
 Multiple immunologic mechanisms may contribute to thyroid cell death, including:
CD8+ cytotoxic T cell–mediated cell death: CD8+ cytotoxic T cells may destroy
thyroid follicular cells.
 Cytokine-mediated cell death: Activation of CD4+ Th1 cells leads to the production
of inflammatory cytokines such as interferon-γ in the thyroid gland, with resultant
recruitment and activation of macrophages and damage to follicles. A less likely
mechanism involves binding of antithyroid antibodies (antithyroglobulin, and
antithyroid peroxidase antibodies) followed by antibody-dependent cell-mediated
cytotoxicity.
Morphology
 The thyroid is usually diffusely enlarged. The capsule is intact, and the
gland is well demarcated from adjacent structures. The cut surface is
pale, yellow-tan, firm, and somewhat nodular. There is extensive
infiltration of the parenchyma by a mononuclear inflammatory
infiltrate containing small lymphocytes, plasma cells, and well-
developed germinal centers .
 The thyroid follicles are atrophic and are lined in many areas by
epithelial cells with abundant eosinophilic, granular cytoplasm, termed
Hürthle cells, which represent a metaplastic response of the normally
low cuboidal follicular epithelium to chronic injury. In fine-needle
aspiration biopsy samples, the presence of Hürthle cells in conjunction
with a heterogeneous population of lymphocytes is characteristic of
Hashimoto thyroiditis. In “classic” Hashimoto thyroiditis, interstitial
connective tissue is increased and may be abundant. Unlike Reidel
thyroiditis , the fibrosis does not extend beyond the capsule of the
gland.
Clinical features
 Hashimoto thyroiditis most often comes to attention as painless
enlargement of the thyroid, usually associated with some degree of
hypothyroidism, in a middle-aged woman. The enlargement of the gland is
generally symmetric and diffuse, but in some cases it may be sufficiently
localized to raise the suspicion of a neoplasm. In the typical case,
hypothyroidism develops gradually. In some patients, however, it may be
preceded by transient thyrotoxicosis caused by disruption of thyroid
follicles and release of thyroid hormones (hashitoxicosis). During this
phase, free T4 and T3 levels are elevated, TSH is diminished, and
radioactive iodine uptake is decreased. As hypothyroidism supervenes, T4
and T3 levels fall, accompanied by a compensatory increase in TSH.
 Individuals with Hashimoto thyroiditis are at increased risk for developing
other autoimmune diseases, both endocrine (type 1 diabetes, autoimmune
adrenalitis) and non-endocrine (systemic lupus erythematosus, myasthenia
gravis, and Sjögren syndrome) .
 They are also at increased risk for development of extranodal marginal
zone B-cell lymphoma within the thyroid gland .
Subacute Lymphocytic (Painless)
Thyroiditis
 Subacute lymphocytic thyroiditis, which is also referred to as painless
thyroiditis, is a presumed autoimmune disease. Most patients have
circulating antithyroid peroxidase antibodies or a family history of other
autoimmune disorders. A similar disease process can occur during the
postpartum period in up to 5% of women (postpartum thyroiditis).
 Morphology. Except for possible mild symmetric enlargement, the
thyroid appears grossly normal. Microscopic examination reveals
lymphocytic infiltration with large germinal centers within the thyroid
parenchyma and patchy disruption and collapse of thyroid follicles.
Unlike Hashimoto thyroiditis, however, fibrosis and Hürthle cell
metaplasia are not prominent.
 Clinical features. Painless thyroiditis usually comes to attention because
of mild, transient hyperthyroidism, painless goiter, or both. Although it
can occur at any age, it is most often seen in middle-aged adults and is
more common in women. Some patients transition from hyperthyroidism
to hypothyroidism before recovery.
Granulomatous Thyroiditis
 Granulomatous thyroiditis (also called De Quervain thyroiditis)
occurs much less frequently than does Hashimoto thyroiditis. The
disorder is most common between 40 and 50 years of age and, like
other forms of thyroiditis, affects women more often than men
(4:1).
 Pathogenesis. Granulomatous thyroiditis is believed to be triggered
by a viral infection. The majority of patients have a history of an
upper respiratory infection just before the onset of thyroiditis. The
disease is seasonal, with occurrences peaking in the summer, and
clusters of cases have been reported in association with
coxsackievirus, mumps, measles, adenovirus, and other viral
infections. Although the pathogenesis of the disease is unclear, one
model suggests that it results from virus-induced host tissue
damage that stimulates a cytotoxic T-lymphocyte response to one
or more thyroid antigens that damages thyroid follicle cells.
Cont’
 Morphology. The gland may be unilaterally or bilaterally enlarged and firm,
with an intact capsule that may adhere to surrounding structures. On cut
section, the involved areas are firm and yellow-white and stand out from
adjacent normal rubbery, brown thyroid gland. Histologic changes are
patchy and depend on the stage of the disease. Early in the active
inflammatory phase, scattered follicles may be disrupted and replaced by
neutrophils forming microabscesses. Later, more characteristic features
appear in the form of aggregates of lymphocytes, activated macrophages,
and plasma cells associated with collapsed and damaged thyroid follicles.
Multinucleate giant cells enclose pools of colloid, hence the designation
granulomatous thyroiditis. In later stages of the disease, a chronic
inflammatory infiltrate and fibrosis may replace the foci of injury.
 Clinical features. Granulomatous thyroiditis is the most common cause of

thyroid pain. There is variable enlargement of the gland.

 Other, less common forms of thyroiditis include Riedel thyroiditis, a rare

disorder characterized by extensive fibrosis involving the thyroid and

contiguous neck structures.
GRAVES DISEASE
 Graves disease is the most common cause of endogenous
hyperthyroidism.
 The disease is characterized by a triad of clinical findings:
 Hyperthyroidism associated with diffuse enlargement of
the gland .
 Infiltrative ophthalmopathy and resultant exophthalmos .
 Localized, infiltrative dermopathy, sometimes called
pretibial myxedema, which is present in a minority of
patients.
 Graves disease has a peak incidence between 20 and 40
years of age. Women are affected as much as 10 times
more frequently than men.
Pathogenesis
 Graves disease is an autoimmune disorder
characterized by the production of
autoantibodies against multiple thyroid proteins,
most importantly the TSH receptor.
 A variety of antibodies that either stimulate or

block the TSH receptor are detected in the

circulation. The most common antibody subtype,
known as thyroid-stimulating immunoglobulin
(TSI).
 Factors that predispose to Graves disease overlap

with risk factors for Hashimoto thyroiditis.

Cont’
 Morphology. The thyroid gland is usually symmetrically enlarged due to
diffuse hypertrophy and hyperplasia of thyroid follicular epithelial cells.
On cut section, the parenchyma has a soft, meaty appearance resembling
muscle. Histologically, the follicle epithelial cells in untreated cases are
tall and more crowded than usual. This crowding often results in the
formation of small papillae that project into the follicle lumen and
encroach on the colloid, sometimes filling the follicles .
 Clinical features. The findings in Graves disease include changes

associated with thyrotoxicosis and others associated uniquely with Graves

disease, such as diffuse hyperplasia of the thyroid, ophthalmopathy, and
dermopathy. The thyroid enlargement may be accompanied by increased
flow of blood through the hyperactive gland, often producing an audible
“bruit.” Sympathetic overactivity produces a characteristic wide, staring
gaze and lid lag, while the ophthalmopathy causes exophthalmos. The
infiltrative dermopathy (pretibial myxedema) is most common in the skin
overlying the shins, where it presents as scaly thickening and induration.
DIFFUSE AND MULTINODULAR GOITER
1. Diffuse
 Diffuse nontoxic (simple) goiter causes enlargement of the entire gland
without producing nodularity. Because the enlarged follicles are filled with
colloid, the term colloid goiter has been applied to this condition. This
disorder occurs in both an endemic and a sporadic distribution.
 Endemic goiter occurs in geographic areas where the soil, water, and food

supply contain low levels of iodine. The lack of iodine leads to decreased
synthesis of thyroid hormone and a compensatory increase in TSH, leading
to follicular cell hypertrophy and hyperplasia and goitrous enlargement. The
ingestion of substances that interfere with thyroid hormone synthesis at
some level, such as vegetables belonging to the Brassicaceae (Cruciferae)
family (e.g., cabbage, cauliflower, Brussels sprouts, turnips, and cassava),
has been documented to be goitrogenic.
 Sporadic goiter can be caused by several conditions, including the ingestion

of substances that interfere with thyroid hormone synthesis. In other

instances, goiter may result from hereditary enzymatic defects that interfere
with thyroid hormone synthesis, all transmitted as autosomal recessive
conditions (dyshormonogenetic goiter).
Morphology
 Two phases can be identified in the evolution of diffuse nontoxic goiter: the
hyperplastic phase and the phase of colloid involution. In the hyperplastic phase,
the thyroid gland is diffusely and symmetrically enlarged, although the increase
is usually modest. The follicles are lined by crowded columnar cells, which may
pile up and form projections similar to those seen in Graves disease. The
accumulation is not uniform throughout the gland, and some follicles are hugely
distended, whereas others remain small. If dietary iodine subsequently increases
or if the demand for thyroid hormone decreases, the stimulated follicle
epithelium involutes to form an enlarged, colloid-rich gland (colloid goiter) In
these cases, the cut surface of the thyroid is usually brown, somewhat glassy,
and translucent. Histologically the follicle epithelium is flattened and cuboidal,
and colloid is abundant during periods of involution
 CLINICAL FEATURES.Most persons with simple goiters are clinically euthyroid.
Therefore, the clinical manifestations are primarily related to mass effects from
the enlarged thyroid gland .Although serum T3 and T4 levels are normal, the
serum TSH is usually elevated or at the upper range of normal, as is expected in
marginally euthyroid individuals. In children, dyshormonogenetic goiter, caused
by a congenital biosynthetic defect, may induce cretinism.
Multinodular Goiter
 With time, recurrent episodes of hyperplasia and involution combine to
produce a more irregular enlargement of the thyroid, termed multinodular
goiter. Virtually all long-standing simple goiters convert into multinodular
goiters. Multinodular goiters produce the most extreme thyroid
enlargements and are more frequently mistaken for neoplasms than any
other form of thyroid disease.
 Pathogenesis It is believed that multinodular goiters arise because of

variations among follicular cells in their response to external stimuli, such as

trophic hormones. If some cells in a follicle have a growth advantage,
perhaps because of acquired genetic abnormalities similar to those that give
rise to adenomas, they may begin to proliferate autonomously, producing a
nodule. Consistent with this model, both polyclonal and monoclonal nodules
coexist within the same multinodular goiter. The follicle hyperplasia and
accumulation of colloid produce physical stress that may lead to rupture of
follicles and vessels followed by hemorrhages, scarring, and calcifications.
With scarring, nodularity appears, which may be accentuated by the
preexisting stromal framework of the gland.
Morphology
 Multinodular goiters are multilobulated, asymmetrically enlarged glands.
The pattern of enlargement is unpredictable and may involve one lobe far
more than the other, producing pressure on midline structures, such as
the trachea and esophagus. In other instances, the goiter grows behind
the sternum and clavicles to produce the intrathoracic or plunging goiter.
On cut section, irregular nodules containing variable amounts of brown,
gelatinous colloid are present. Older lesions have areas of hemorrhage,
fibrosis, calcification, and cystic change. The microscopic appearance
includes colloid-rich follicles lined by flattened, inactive epithelium and
areas of follicle hyperplasia, accompanied by degenerative changes
related to physical stress.
 CLINICAL FEATURES. The dominant clinical features of multinodular goiter
are those caused by mass effects. In addition to their cosmetic effects,
goiters may cause airway obstruction, dysphagia, and compression of
large vessels in the neck and upper thorax (superior vena cava syndrome).
Most patients are euthyroid or have subclinical hyperthyroidism.
NEOPLASMS OF THE THYROID
 Several criteria provide clues to the nature of a thyroid
nodule:
 Solitary nodules, nodules in younger patients, and nodules

in males are more likely to be neoplastic.

 A history of radiation treatment to the head and neck

region is associated with an increased incidence of thyroid

malignancy.
 Functional nodules that take up radioactive iodine in

imaging studies (hot nodules) are much more likely to be

benign.
 Ultimately, morphologic evaluation of a given thyroid

nodule by fine-needle aspiration or surgical resection

provides the most definitive information about its nature,
Thyroid Adenomas
 Adenomas of the thyroid are typically discrete, solitary masses, derived
from follicle epithelium, and hence they are also known as follicular
adenomas.
 Pathogenesis. Somatic mutations that lead to constitutive activation of the
TSH receptor signaling pathway are found in toxic adenomas and toxic
multinodular goiter. Gain-of-function mutations—most often in the gene
encoding the TSH receptor (TSHR), and less commonly, the α-subunit of
Gs (GNAS)— cause follicular cells to secrete thyroid hormone independent
of TSH stimulation (“thyroid autonomy”). This leads to hyperthyroidism
and produces a functional “hot” nodule on imaging. Approximately one-
third of toxic adenomas also harbor activating mutations of enhancer of
zeste, homolog 1 (EZH1), which encodes a histone methyltransferase that
functions as an epigenetic regulator of gene expression.In contrast, a
minority (20% to 40%) of nonfunctioning follicular adenomas harbor
oncogenic mutations of RAS, and a smaller percentage (5% to 10%)
express fusion proteins containing the nuclear receptor PPARγ.
Morphology
 The typical thyroid adenoma is a solitary, spherical, encapsulated lesion that is
demarcated by a well-defined, intact capsule.
 In freshly resected specimens, the adenoma bulges from the cut surface and
compresses the adjacent thyroid. The color ranges from gray-white to red-
brown, depending on the cellularity of the adenoma and its colloid content.
Areas of hemorrhage, fibrosis, calcification, and cystic change, similar to those
encountered in multinodular goiters, are common in follicular adenomas,
particularly within larger lesions. Microscopically, the constituent cells often
form uniformappearing follicles that contain colloid. The follicular growth
pattern is usually quite distinct from the adjacent nonneoplastic thyroid. The
neoplastic cells show little variation in cell size, shape, or nuclear morphology,
and mitotic figures are rare. Occasionally the neoplastic cells acquire brightly
eosinophilic granular cytoplasm (oxyphil or Hürthle cell change).
 CLINICAL FEATURES. Many follicular adenomas present as solitary painless
masses that are discovered on routine physical examination. Larger masses may
produce local symptoms, such as difficulty in swallowing. Nonfunctioning
adenomas take up less radioactive iodine than does normal thyroid parenchyma
and on radionuclide scanning appear as cold nodules.
Thyroid carcinoma
 The major subtypes of thyroid carcinoma and their relative frequencies are as
follows:
 Papillary thyroid carcinoma (PTC), including “conventional” PTC and the
“encapsulated follicular variant” (80% to 85%% of cases). This category includes
the newly described lesion known as “noninvasive follicular thyroid neoplasm
with papillary-like nuclear features,” a low-grade neoplasm with such a minimal
risk of recurrence that “carcinoma” has been removed from its name.
 Follicular carcinoma (10% to 15% of cases)
 Poorly differentiated and anaplastic (undifferentiated) carcinoma (<5% of cases).
 Medullary carcinoma(5% of cases).
 Most thyroid carcinomas are derived from thyroid follicle epithelium (except
medullary carcinoma, which is derived from parafollicular C cells), and, of these,
the vast majority are well-differentiated lesions.
 Papillary microcarcinoma as a precursor to conventional PTC.
 Noninvasive thyroid neoplasm with papillarylike nuclear features as a precursor
to invasive encapsulated follicular variant PTC .
 Nonfunctioning follicular adenoma as a precursor to follicular carcinoma.
Pathogenesis
1.Driver Mutations:
 Conventional PTCs have two defining genetic abnormalities: translocations that

result in gene fusions of RET or NTRK, and point mutations in BRAF.

 Follicular neoplasms. In contrast to papillary carcinomas, follicular neoplasms

are often associated with gain-offunction mutations in RAS.

 Poorly differentiated and anaplastic (undifferentiated) carcinomas. These highly

aggressive and lethal tumors can arise de novo, or, much more commonly, by
“de-differentiation” of a papillary or follicular thyroid carcinoma. In addition to
driver mutations that are also seen in well-differentiated thyoid cancers, three
recurrent genetic “hits”—point mutations of TP53, beta-catenin (CTNNB1), and
TERT.
 Medullary thyroid carcinomas. Familial medullary thyroid carcinomas occur in

multiple endocrine neoplasia, type 2 (MEN-2) and are associated with germline
RET mutations that lead to constitutive activation of the receptor.
2.Environmental Factors. The major risk factor predisposing to thyroid cancer is
exposure to ionizing radiation, particularly during the first two decades of life.
Deficiency of dietary iodine (and by extension, goiter) is associated with a higher
frequency of follicular lesions.
THE END!!